Pharmaceutical composition for use as a contraceptive

ABSTRACT

A pharmaceutical composition comprises, as a first active agent, 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent, 17α-ethinylestradiol (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients.  
     In a specific embodiment, the composition consists of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein said daily dosage units comprises the combination of drospirenone and ethinylestradiol. The composition may further comprise 7 or less daily dosage units containing no active agent or containing ethinylestradiol alone.

FIELD OF THE INVENTION

[0001] The present invention relates to a pharmaceutical compositioncomprising drospirenone and ethinylestradiol, a method of providingdissolution of drospirenone, methods of inhibiting ovulation byadministration of drospirenone and the use of drospirenone andethinylestradiol for inhibiting ovulation.

BACKGROUND OF THE INVENTION

[0002] Oral contraceptives containing a combination of a gestagen and anestrogen component have been used since the 1960's. The earliestcontraceptive preparations consisted of 21 tablets containing thecombination of active agents and 7 tablets containing no active agent,and the amount of each active agent was the same in each tablet (theso-called one-phase preparations). Subsequently, preparations weredeveloped that consisted of tablets containing different amounts andratios of the active agents over the cycle of administration (theso-called multiple-phase preparations).

[0003] Contraceptive reliability is mainly provided by the gestagencomponent. The daily dosage should be at least the minimum of what isneeded for the gestagen in question to inhibit ovulation effectively.The estrogen component acts to increase the ovulation inhibitory effectof gestagen and to ensure cycle stability. Since the introduction oforal contraceptives, the daily dosage of gestagen has been reducedthrough the development of new and more efficient gestagens than werepresent in the earlier contraceptive preparations. It has also beenpossible to reduce the daily dosage of estrogen.

[0004] 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) is known from DE 26 52 761 in which itsuse as a diuretic compound is disclosed.

[0005] In DE 30 22 337, the gestagen-like activity of the compound andits consequent utility as a contraceptive agent is described at dosagelevels of 0.5-50 mg of drospirenone per day. It is also noted that themechanism of action of the compound is very similar to that of thenatural corpus luteum hormone progesterone, and that it does not giverise to increased blood pressure for which reason it may beadministrated to women who have or are at risk of developing increasedblood pressure. It is further described that drospirenone may beadministered together with ethinylestradiol in an amount of 0.03-0.05 mgper day.

[0006] DE 30 51 166 discloses the use of the drospirenone for thetreatment of gynaecological irregularities and for contraception at adosage level of 0.5-50 mg per day.

[0007] EP 398 460 discloses the use of drospirenone for the treatment ofandrogen-induced disorders, aldosterone-induced disorders and hormonalirregularities as well as for contraception at dosage levels of 0.5-50mg, preferably 1-10 mg per day. Ethinylestradiol may be co-administeredat a level of 0.02-0.04 mg per day.

[0008] U.S. Pat. No. 5,756,490 discloses pharmaceutical combinationpreparations comprising 23 or 24 dosage units containing a combinationof a gestagen and an estrogen and 4-10 dosage units containing estrogenalone: Drospirenone is mentioned as a possible, but not preferred,gestagenic compound and ethinylestradiol is mentioned as a possible, butnot preferred, estrogenic compound.

SUMMARY OF THE INVENTION

[0009] In the course of research leading to the present invention, ithas surprisingly been found that a hitherto undisclosed minimum dosagelevel of drospirenone is required for reliable contraceptive activity.Similarly, a preferred maximum dosage has been identified at whichunpleasant side effects, in particular excessive diuresis, maysubstantially be avoided.

[0010] Accordingly, in a first aspect, the present invention relates toa pharmaceutical composition comprising, as a first active agent,6β,6β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone(drospirenone) in an amount corresponding to a daily dosage, onadministration of the composition, of from about 2 mg to about 4 mg,and, as a second active agent, 17α-ethinylestradiol (ethinylestradiol)in an amount corresponding to a daily dosage of from about 0.01 mg toabout 0.05 mg, together with one or more pharmaceutically acceptablecarriers or excipients.

[0011] Apart form the active substances themselves, it is envisaged thatan ester or prodrug of drospirenone may be employed in the presentcomposition, e.g. an oxyiminopregnane carbolactone as disclosed in WO98/24801. Likewise, it is envisaged that esters or ethers ofethinylestradiol may be included in the composition.

[0012] In a further aspect, the invention relates to a method ofinhibiting ovulation in a mammal, in particular a human, comprisingadministering to said mammal, drospirenone in an amount in the range offrom about 2 mg to about 4 mg of per day, together with ethinylestradiolin an amount of from about 9.01 mg to about 0.05 mg per day, saidamounts being effective to inhibit ovulation in said mammal.

[0013] In a still further aspect, the invention relates to the use ofdrospirenone combined with ethinylestradiol for preparing apharmaceutical preparation for the inhibition of ovulation in a mammal,in particular a human, the composition comprising an amount ofdrospirenone corresponding to a daily dosage, on administration of thecomposition, of from about 2 mg to about 4 mg, and comprising an amountof ethinylestradiol corresponding to a daily dosage, on administrationof the composition, of from about 0.01 to about 0.05 mg.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The invention is further described with reference to the drawingsin which

[0015]FIG. 1 is a graph showing the in vitro dissolution rate ofdrospirenone from tablet cores, V1-V7 being batches containingmicronized drospirenone, and V8 being a batch containingmacrocrystalline drospirenone;

[0016]FIG. 2 is a graph showing the in vitro dissolution rate ofdrospirenone from tablet cores, different lines representing differenttest batches;

[0017]FIG. 3 is a graph showing the in vitro dissolution rate ofdrospirenone from film-coated tablets, different lines representingdifferent test batches;

[0018]FIG. 4 is a graph showing the in vitro dissolution rate ofethinylestradiol from tablet cores, different lines representingdifferent test batches; and

[0019]FIG. 5 is a graph showing the in vitro dissolution rate ofethinylestradiol from film-coated tablets, different lines representingdifferent test batches.

DETAILED DISCLOSURE OF THE INVENTION

[0020] Drospirenone, which may be prepared substantially as describedin, e.g., U.S. Pat. No. 4,129,564 or WO 98/06738, is a sparingly solublesubstance in water and aqueous buffers at various pH values.Furthermore, drospirenone is rearranged to an inactive isomer under acidconditions and hydrolysed under alkaline conditions. To ensure goodbioavailability of the compound, it is therefore advantageously providedin a form that promotes rapid dissolution thereof.

[0021] It has surprisingly been found that when drospirenone is providedin micronized form (so that particles of the active substance have asurface area of more than 10,000 cm²/g, and the following particle sizedistribution as determined under the microscope: not more than 2particles in a given batch with a diameter of more than 30 μm, andpreferably ≦20 particles with a diameter of ≧10 μm and ≦30 μm) in apharmaceutical composition, rapid dissolution of the active compoundfrom the composition occurs in vitro (“rapid dissolution” is defined asthe dissolution of at least 70% over about 30 minutes, in particular atleast 80% over about 20 minutes, of drospirenone from a tabletpreparation containing 3 mg of drospirenone in 900 ml of water at 37° C.determined by the USP XXIII Paddle Method using a USP dissolution testapparatus 2 at 50 rpm). Instead of providing the drospirenone inmicronized form, it is possible to dissolve it in a suitable solvent,e.g. methanol or ethyl acetate, and spray it onto the surface of inertcarrier particles followed by incorporation of the particles containingdrospirenone on their surface in the composition.

[0022] Without wishing to be limited to any particular theory, itappears that the in vitro dissolution rate of drospirenone is connectedto the dissolution rate in vivo resulting in rapid absorption ofdrospirenone in vivo on oral administration of the compound. This is anadvantage because isomerization of the compound in the gastricenvironment and/or hydrolysis in the intestine is substantially reduced,leading to a high bioavailability of the compound.

[0023] With respect to ethinylestradiol which is also a sparinglysoluble substance, though less sensitive to degradation thandrospirenone under conditions prevailing in the gastrointestinal tract,it is also an advantage to provide it in micronized form or sprayed froma solution, e.g. in ethanol, onto the surface of inert carrierparticles. This has the added advantage of facilitating a morehomogenous distribution of the ethinylestradiol throughout thecomposition which might otherwise be difficult to obtain becauseethinylestradiol is incorporated in extremely small amounts. Whenethinylestradiol is provided in micronized form, it preferably has thefollowing particle size distribution as determined under the microscope:100% of the particles have a diameter of ≦15.0 μm, 99% of the particleshave a diameter of ≦12.5 μm, 95% of the particles have a diameter of≦10.0 μm, and 50% of the particles have a diameter of ≦3.0 μm.Furthermore, no particle is larger than 20 μm, and ≦10 particles have adiameter of ≧15 μm and ≦20 μm.

[0024] To obtain a more rapid rate of dissolution, it is preferred toinclude carriers or excipients which act to promote dissolution of bothactive substances. Examples of such carriers and excipients includesubstances that are readily soluble in water such as cellulosederivatives, carboxymethylcellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, gelled starch, gelatin orpolyvinylpyrrolidone. In particular, it appears as thoughpolyvinylpyrrolidone might be particularly helpful to promotedissolution.

[0025] The composition of the invention preferably comprisesdrospirenone in an amount corresponding to a daily dosage of from about2.5 mg to about 3.5 mg, in particular about 3 mg. The amount ofethinylestradiol preferably corresponds to a daily dosage of from about0.015 mg to about 0.04 mg, in particular from about 0.015 mg to about0.03 mg. More particularly, the present composition comprises an amountof drospirenone corresponding to a daily dosage of from about 3.0 toabout 3.5 mg and ethinylestradiol in an amount corresponding to fromabout 0.015 to about 0.03 mg.

[0026] Apart from its ability to inhibit ovulation, the composition ofthe invention has been found to possess pronounced anti-androgenicproperties and may therefore be used in the prevention or treatment ofandrogen-induced disorders, in particular acne. Such use may beindependent from or concomitant with the use as a contraceptivedisclosed above. Furthermore, since drospirenone is an aldosteroneantagonist, it has diuretic properties and is therefore suitable forcounteracting the water-retentive properties of ethinylestradiol.

[0027] In a particular embodiment, the invention relates to apharmaceutical preparation consisting of a number of separately packagedand individually removable daily dosage units placed in a packaging unitand intended for oral administration for a period of at least 21consecutive days, wherein each of said daily dosage units comprises acombination of drospirenone in an amount of from about 2 mg to about 4mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg.

[0028] In one embodiment, the preparation further comprises 7 or lesssaid daily dosage units containing no active agent. Alternatively, it ispossible to include, in the dosage regimen, a period of 7 days or lessduring which no dosage units are ingested. For compliance reasons,however, it may be preferred to include an appropriate number of blanksin the preparation, in which case the total number of daily dosage unitsin the preparation is at least 28. The inclusion of blanks, or thepill-free days, will then trigger withdrawal bleeding.

[0029] The preparation may be a one-phase composition, i.e. apreparation wherein the amounts of either active agent remains constantfor the entire at least 21-day period, or the amounts of either or bothactive agents may be varied over the at least 21-day period to generatea multiple-phase preparation, e.g. a two- or three-phase preparation,substantially as disclosed in, e.g., EP 148 724. In case ofmultiple-phase preparation, it may be possible to include a naturalestrogen such as estradiol, e.g. in an amount of from about 0.5 mg toabout 4 mg per day, instead of ethinylestradiol.

[0030] In suitable embodiments of the present preparation, the number ofdaily dosage units comprising the combination of drospirenone andethinylestradiol may be 21, 22, 23 or 24, and the number of daily dosageunits containing no active agent may then be 7, 6, 5 or 4, as the casemay be. In a further embodiment of the present preparation, the numberof daily dosage units comprising the combination of drospirenone andethinylestradiol is 28, or a multiple of 28 such as 2-4, in particular 2or 3, times 28.

[0031] In an alternative embodiment, the invention relates to acontraceptive preparation consisting of a number of separately packagedand individually removable daily dosage units placed in a packaging unitand intended for oral administration for a period of at least 28consecutive days, wherein at least 21 of said daily dosage unitscomprises a combination of drospirenone in an amount of from about 2 mgto about 4 mg and ethinylestradiol in an amount from about 0.01 to about0.05 mg, and wherein 7 or less of said daily dosage units containethinylestradiol alone in an amount from about 0.01 to about 0.05 mg.

[0032] By including an appropriate number of dosage units comprisingethinylestradiol alone, high contraceptive reliability, low folliculardevelopment and satisfactory cycle control with little or nointermenstrual bleeding may be obtained.

[0033] In this case, too, the preparation may be one in which theamounts of either active agent remains constant for the entire at least21-day period (i.e. a two-phase preparation), or the amounts of eitheror both active agents may be varied over the at least 21-day period togenerate a multiple-phase preparation, e.g. a three- or four-phasepreparation, substantially as disclosed in, e.g., EP 148 724. In case ofmultiple-phase preparation, it may be possible to include a naturalestrogen such as estradiol, e.g. in an amount of from about 0.5 mg toabout 4 mg per day, instead of ethinylestradiol.

[0034] In suitable embodiments of the present preparation, the number ofdaily dosage units comprising the combination of drospirenone andethinylestradiol may be 21, 22, 23 or 24, and the number of daily dosageunits containing ethinylestradiol alone may then be 7, 6, 5 or 4, as thecase may be.

[0035] In one embodiment of the present method of inhibiting ovulation,the method comprises administering, to said mammal, on each day of atleast 21 consecutive days, a daily dosage unit comprising a combinationof drospirenone in an amount of from about 2 mg to about 4 mg andethinylestradiol in an amount from about 0.01 to about 0.05 mg, followedby administering, on each day of 7 or less consecutive days, a dailydosage unit containing no active agent, or alternatively, administeringno dosage units for 7 days or less.

[0036] In suitable embodiments of this method, the daily dosage unitscomprising the combination of drospirenone and ethinylestradiol may beadministered for 21, 22, 23 or 24 consecutive days, and the daily dosageunits containing no active agent may then be administered for 7, 6, 5 or4 consecutive days, as appropriate. Furthermore, the daily dosage unitscomprising the combination of drospirenone and ethinylestradiol may beadministered for 28 consecutive days. In a variant of this embodiment,the daily dosage units comprising the combination of drospirenone andethinylestradiol are administered for 2-4, preferably 2 or 3, times 28consecutive days, followed by administration of the daily dosage unitscomprising the combination of drospirenone and ethinylestradiol for 21,22, 23 or 24 consecutive days and subsequently administration of thedaily dosage units containing no active agent, or administration of nodaily dosage units, for 7, 6, 5₁ or 4 consecutive days.

[0037] Alternatively, the present method comprises administering, oneach day of at least 21 consecutive days, a daily dosage unit comprisinga combination of drospirenone in an amount of from about 2 mg to about 4mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg,followed by administering, on each day of 7 or less consecutive days, adaily dosage unit containing ethinylestradiol alone in an amount of fromabout 0.01 mg to about 0.05 mg.

[0038] In this alternative method, the daily dosage units comprising thecombination of drospirenone and ethinylestradiol may suitably beadministered for 21, 22, 23 or 24 consecutive days, and wherein thedaily dosage units comprising ethinylestradiol alone may then beadministered for 7, 6, 5 or 4 consecutive days, as appropriate. In afurther embodiment of the method, the daily dosage units comprising thecombination of drospirenone and ethinylestradiol are administered for2-4, preferably 2 or 3, times 28 consecutive days, followed byadministration of the daily dosage units comprising the combination ofdrospirenone and ethinylestradiol for 21 consecutive days andsubsequently administration of the daily dosage units comprisingethinylestradiol alone for 7 consecutive days.

[0039] For use according to the invention, the pharmaceuticalpreparation may suitably be in the form of a number of separatelypackaged and individually removable daily dosage units placed in apackaging unit and intended for oral administration for a period of atleast 21 consecutive days, wherein each of said daily dosage units eachcomprises a combination of drospirenone in an amount of from about 2 mgto about 4 mg and ethinylestradiol in an amount from about 0.01 to about0.05 mg.

[0040] As indicated above, the preparation may further comprise 7 orless daily dosage units containing no active agent (or may contain 7 orless empty “places”, e.g. in the form of empty blisters in a blisterpack, marking the days on which no daily dosage units are administered).

[0041] Alternatively, the pharmaceutical preparation may be in the formof a number of separately packaged and individually removable dailydosage units placed in a packaging unit and intended for oraladministration for a period of at least 28 consecutive days, wherein atleast 21 of said daily dosage units each comprises a combination ofdrospirenone in an amount of from about 2 mg to about 4 mg andethinylestradiol in an amount of from about 0.01 to about 0.05 mg, saidpackaging unit further comprising 7 or less daily dosage unitscomprising ethinylestradiol alone in an amount of from about 0.01 mg toabout 0.05 mg.

[0042] The composition of the invention may be formulated in any mannerknown in the pharmaceutical art. In particular, as indicated above, thecomposition may be formulated by a method comprising providingdrospirenone and, if desired, ethinylestradiol in micronized form insaid unit dosage form, or sprayed from a solution onto particles of aninert carrier in admixture with one or more pharmaceutically acceptableexcipients that promote dissolution of the drospirenone andethinylestradiol so as to promote rapid dissolution of drospirenone andpreferably ethinylestradiol on oral administration. Examples of suitableexcipients include fillers, e.g. sugars such as lactose, glucose orsucrose, sugar alcohols such as mannitol, sorbitol or xylitol, starchsuch as wheat, corn or potato starch, modified starch or sodium starchglycolate, lubricants such as talc, magnesium stearate, calciumstearate, colloidal silica or stearic acid, and binders such aspolyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl celluloseor gelatin, for making oral. dosage forms such as tablets, pills orcapsules.

[0043] Tablets may conveniently be coated with a suitable film-formingagent, e.g. hydroxypropylmethyl cellulose, hydroxypropyl cellulose orethyl cellulose, to which a suitable excipient may optionally be added,e.g. a softener such as glycerol, propylene glycol, diethylphthalate orglycerol triacetate, filler such as sucrose, sorbitol, xylitol, glucoseor lactose, a colorant such as titanium hydroxide, etc.

[0044] The present composition may also be formulated in liquid form,e.g. as a solution, suspension or emulsion, together with conventionaldiluents or excipients in a manner known per se in the pharmaceuticalart.

[0045] A packaging unit comprising the daily dosage units describedabove may be prepared in a manner analogous to that of making other oralcontraceptives. This may for instance be a conventional blister pack orany other form known for this purpose, for instance a pack comprisingthe appropriate number of dosage units (in this case at least 21, or forparticular applications, 28 or a multiple of 28) in a sealed blisterpack with a cardboard, paperboard, foil or plastic backing and enclosedin a suitable cover. Each blister container may conveniently be numberedor otherwise marked, e.g. starting with the first of the at least 21dosage units that contain the combination of drospirenone andethinylestradiol, optionally followed by 7 or less empty blisters or bythe 7 or less dosage units that contain no active agent or that onlycontain ethinylestradiol (although the numbering may also start with thefirst of the 7 or less dosage units that only contain ethinylestradiol).

[0046] It is also envisaged that the present composition may be in theform of a parenteral formulation such as a subcutaneous implant ortransdermal formulation. For making implants, the active agents maysuitably be formulated together with one or more polymers that aregradually eroded or degraded when in use, e.g. silicone polymers,ethylene vinylacetate, polyethylene or polypropylene.

[0047] Where transdermal formulations are concerned, they may beprepared in the form of matrices or membranes or as fluid or viscousformulations in oil or hydrogels. For transdermal patches, an adhesivewhich is compatible with the skin should be included, such aspolyacrylate, a silicone adhesive or polyisobutylene, as well as a foilmade of, e.g. polyethylene, polypropylene, ethylene vinylacetate,polyvinylchloride, polyvinylidene chloride or polyester, and a removableprotective foil made from, e.g., polyester or paper coated with siliconeor a fluoropolymer. For the preparation of transdermal solutions orgels, water or organic solvents or mixtures thereof may be used.Transdermal gels may furthermore contain one or more suitable gellingagents or thickeners such as silicone, tragacanth, starch or starchderivatives, cellulose or cellulose derivatives or polacrylic acids orderivatives thereof. Transdermal formulations may also suitably containone or more substances that enhance absorption though the skin, such asbile salts or derivatives thereof and/or phospholipids. Suitabletransdermal formulations may, for instance, be made in a manneranalogous to that described in WO 94/04157 for 3-ketodesogestrel.Alternatively, transdermal formulations may be prepared according to amethod disclosed in, e.g., B W Barry, “Dermatological Formulations,Percutaneous Absorption”, Marcel Dekker Inc., New York-Basel, 1983, or YW Chien, “Transdermal Controlled Systemic Medications”, Marcel DekkerInc., New York-Basel, 1987.

[0048] The present invention is further described in the followingexamples which are not in any way intended to limit the scope of theinvention as claimed.

EXPERIMENTAL Example 1

[0049] Preparation of Tablets Containing Drospirenone andEthinylestradiol Tablet cores of the following composition micronizeddrospirenone 3.00 mg micronized ethinylestradiol 0.03 mg lactosemonohydrate 48.17 mg corn starch 14.40 mg modified starch 9.60 mgpolyvinylpyrrolidone 25,000 4.00 mg magnesium stearate 0.80 mg

[0050] were prepared by charging a fluidized bed granulator with 31.68kg corn starch, 21.12 kg modified starch, 6.60 micronized drospirenone,0.066 kg micronized ethinylestradiol and 105.974 kg lactose monohydrateand activating the fluidized bed. An aqueous solution of 8.80 kgpolyvinylpyrrolidone 25,000 in 46.20 kg purified water was sprayedcontinuously onto the fluidized bed while drying by heating the airstream of the fluidized bed. At the end of the process 1.76 kg magnesiumstearate was sucked into the granulator and mixed with the granules bymaintaining the fluidized bed. The resulting granulate was pressed intotablet cores by compression using a rotary tablet press.

[0051] 2.22464 kg of hydroxypropylmethylcellulose and 0.44528 macrogol6000 were dissolved in 14.67 kg purified water. 0.44528 kg talc, 1.22430kg titanium dioxide and 0.06050 kg ferric oxide pigment were suspendedin 10.26 kg purified water with stirring and homogenized. The solutionand suspension were combined and used to coat the tablet cores bycontinuous application of the coating suspension in a coater.

Example 2

[0052] Dissolution of Drospirenone From Tablets

[0053] The rate of dissolution of drospirenone from the tablets preparedin Example 1 was determined by the USP XXIII Paddle Method using a USPDissolution Test Apparatus 2 including 6 covered glass vessels and 6paddles. Tablets were placed in 900 ml water at a temperature of 37° C.(±0.5° C.) and stirred at 50 rpm.

[0054] The results appear from FIGS. 1, 2 and 4. From FIG. 1, it appearsthat the batch numbered V8 containing macrocrystalline drospirenone (butotherwise identical to the tablets prepared in Example 1) exhibited anextremely slow dissolution rate of drospirenone, whereas all batchescontaining micronized drospirenone exhibited a dissolution rate of morethan 70% within 30 minutes.

[0055]FIG. 2 and FIG. 4 shows the results of dissolution of drospirenonefrom tablet cores and film-coated tablets, respectively. In both casesmore than 70% of the active agent is dissolved within 30 minutes. Thus,the film coating did not significantly influence the rate ofdissolution.

Example 3

[0056] Dissolution Rate of Ethinylestradiol From Tablets In Vitro

[0057] The rate of dissolution of ethinylestradiol from tablets preparedas described in Example 1 was determined according to the USP PaddleMethod as described in Example 2 for drospirenone. The results appearfrom FIGS. 3 and 5 showing the dissolution rates from tablet cores andfilm-coated tablets, respectively. In both cases, more than 70% of theactive agent was dissolved within 30 minutes. Thus, the film coating didnot significantly influence the rate of dissolution.

Example 4

[0058] Bioavailability of Drospirenone and Ethinylestradiol From TabletsContaining 3 mg of Drospirenone and 0.03 mg Ethinylestradiol

[0059] 42 healthy women between 18 and 35 years of age were included inan open-label crossover study after their informed consent had beenobtained. The aim of the study was to investigate the relativebioavailability of drospirenone and ethinylestradiol from a tabletformulation containing 3 mg drospirenone and 0.03 mg ethinylestradiolwith reference to an oral suspension containing 6 mg of drospirenone and0.06 mg ethinylestradiol per vial.

[0060] The bioavailability was determined using serum concentrations ofeach active agent as parameters. Compared to the oral suspension, therelative bioavailability of drospirenone and ethinylestradiol from thetablets is 107% and 117%, respectively. It was therefore concluded thatboth drospirenone and ethinylestradiol are completely released from thetablets in vivo.

[0061] The absolute bioavailability of drospirenone was determined intwo studies to be 76%±13% after oral administration of 2 mg drospirenoneto 8 young healthy women and 85%±24% after oral administration of amicrocrystalline suspension containing 3.13 mg drospirenone to 6postmenopausal women.

[0062] The oral bioavaliability of ethinylestradiol was determined inseveral studies, and mean values of from 36% to 59% were reported in theliterature, indicating a first-pass effect.

Example 5

[0063] Contraceptive Efficacy of Formulations Containing Drospirenoneand Ethinylestradiol

[0064] An open-label, randomized trial with 52 female volunteers aged20-35 years whose informed consent had been obtained included 1pre-treatment cycle, 3 treatment cycles with two different tabletcontaining 2 mg and 3 mg drospirenone, respectively, but otherwisecorresponding to the tablets prepared in Example 1, and a follow-upphase. A wash-out phase of 1 month preceded the treatment.

[0065] At defined time points, selected central and peripheralparameters were investigated: LH, FSH, 17β-estradiol, progesterone,cervical score, “spinnbarkeit”, fern phenomenon. Ovarian function waschecked by ultrasound. In addition, SHBG, CBG, prolactine, totaltestosterone, androstqnedione, DHEA-S and selected metabolicparameters₁(serum glucose, triglycerides, cholesterol, HDL, LDL) wereexamined. Blood pressure, heart rate, body weight and cycle control weredocumented.

[0066] The results of the study showed that both LH and FSH were clearlysuppressed with both trial preparations. Accordingly, the secretion ofestradiol and progesterone were greatly reduced over all three treatmentcycles with the exception of 3 volunteers receiving the 2 mgdrospirenone preparation. This result was, in principle, confirmed bythe accompanying ultrasound examinations. Follicular ripening occurredin several cases with both trial preparations. Although three ovulationswere diagnosed with the preparation containing 2 mg drospirenone (one ofwhich was described as “equivocal” and the other as a “tablet-takingerror”), no differences were demonstrable statistically (p>0.05) betweenthe two trial preparations as regards the hormones LH, FSH, estradioland progesterone, and the parameter “ovulation during the treatmentcycles”. In keeping with the hormones, cervical function was greatlylimited and the “spinnbarkeit” and crystallisability of the cervicalmucus was greatly reduced with both trial preparations. Prolactinincreased minimally and SHBG and CBG distinctly with both preparations.Triglycerides and HDL levels increased with both trial preparations,while LDL levels decreased. Total cholesterol was largely unchanged inboth treatment groups. Oral glucose tolerance remained virtuallyunchanged or was slightly decreased. Testosterone, androstenedione andDHEA-S decreased minimally.

[0067] The subjective and objective tolerance was good with bothtreatments. This was also the case for cycle control with the exceptionof the first cycle with 2 mg drospirenone. Blood pressure, heart rateand body weight remained constant in the majority of cases or showed aslight tendency to decrease.

[0068] After three months' treatment, it was concluded:

[0069] The two trial preparations were equally good as regards thesubjective and objective tolerance.

[0070] No negative metabolic effects were observed with eitherpreparation. HDL was influenced positively in the sense of an increase.

[0071] The results confirmed the results of earlier studies that the 2mg drospirenone preparation was in the₁ threshold region of ovulationinhibition, whereas the 3₁ mg drospirenone preparation had ademonstrable ovulation-inhibiting effect in all cases examined.

[0072] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0073] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The preceding preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0074] The entire disclosure of all applications, patents andpublications, cited above and below, and of corresponding U.S.application Ser. No. 09/386,274, are hereby incorporated by reference.

[0075] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A pharmaceutical composition comprising, as a first active agent,6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactonei(drospirenone) in an amount corresponding to a daily dosage, onadministration of the composition, of from about 2 mg to about 4 mg,and, as a second active agent, 17α-ethinylestradiol (ethinylestradiol)in an amount corresponding to a daily dosage of from about 0.01 mg toabout 0.05 mg, together with one or more pharmaceutically acceptablecarriers or excipients.
 2. A composition according to claim 1 whereinthe drospirenone is in micronized form or sprayed from a solution ontoparticles of an inert carrier.
 3. A composition according to claim 1 or2, comprising drospirenone in an amount corresponding to a daily dosageof from about 2.5 mg to about 3.5 mg, in particular about 3 mg.
 4. Acomposition according to claim 1 wherein the ethinylestradiol is inmicronized form or sprayed from a solution onto particles of an inertcarrier.
 5. A composition according to claim 1, comprisingethinylestradiol in an amount corresponding to a daily dosage of fromabout 0.015 mg to about 0.04 mg, in particular from about 0.02 mg toabout 0.03 mg.
 6. A composition according to claim 1, comprising anamount of drospirenone corresponding to a daily dosage of from about 3.0to about 3.5 mg and ethinylestradiol in an amount corresponding to fromabout 0.015 to about 0.03 mg, in particular comprising an amount ofdrospirenone corresponding to a daily dosage of about 3.0 mg andethinylestradiol in an amount corresponding to a daily dosage of 0.03mg.
 7. A composition according to claim 1 wherein the pharmaceuticallyacceptable carrier or excipient is selected so as to promote rapiddissolution of the first and second active agents.
 8. A compositionaccording to claim 1 wherein at least 70% of the first and second activesubstance are released within 30 minutes of administration thereof.
 9. Acomposition according to claim 8, wherein at least 80% of the first andsecond active agents are released within 20 minutes of administrationthereof.
 10. A pharmaceutical preparation consisting of a number ofseparately packaged and individually removable daily dosage units placedin a packaging unit and intended for oral administration for a period ofat least 21 consecutive days,.wherein said daily dosage units comprisesa combination of drospirenone in an amount of from about 2 mg to about 4mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg.11. A preparation according to claim 10, which additionally comprises 7or less daily dosage units containing no active agent intended for oraladministration subsequent to the period of at least 21 consecutive days,the total number of daily dosage units being at least
 28. 12. Apreparation according to claim 10 or 11, wherein the number of dailydosage units comprising the combination of drospirenone andethinylestradiol is 21, 22, 23 or 24, and wherein the number of dailydosage units containing no active agent is 7, 6, 5 or
 4. 13. Apreparation according to claim 10, wherein the number of daily dosageunits comprising the combination of drospirenone and ethinylestradiol is28, or a multiple of 28 such as 2-4, in particular 2 or 3, times
 28. 14.A preparation according to claim 13, which additionally comprises anumber of daily dosage units comprising the combination of drospirenoneand ethinylestradiol of 21, 22, 23 or 24, and a number of daily dosageunits containing no active agent of 7, 6, 5 or
 4. 15. A preparationaccording to claim 10, wherein the at least 21 daily dosage unitscomprise drospirenone and ethinylestradiol in micronized form or sprayedfrom a solution onto particles of an inert carrier.
 16. A preparationaccording to claim 10 wherein the at least 21 daily dosage unitscomprise drospirenone in an amount of from about 2.5 mg to about 3.5 mg,in particular about 3 mg, and ethinylestradiol in an amount of fromabout 0.015 mg to about 0.04 mg, in particular from about 0.015 mg toabout 0.03 mg.
 17. A preparation according to claim 10, wherein the atleast 21 daily dosage units comprise drospirenone in an amount of fromabout 3.0 to about 3.5 mg and ethinylestradiol in an amountcorresponding to from about 0.015 to about 0.03 mg.
 18. A pharmaceuticalpreparation consisting of a number of separately packaged andindividually removable daily dosage units placed in a packaging unit andintended for oral administration for a period of at least 28 consecutivedays, wherein at least 21 of said daily dosage units comprises acombination of drospirenone in an amount of from about 2 mg to about 4mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg,and wherein 7 or less of said daily dosage units containethinylestradiol alone in an amount from about 0.01 to about 0.05 mg.19. A preparation according to claim 18, wherein the number of dailydosage units comprising the combination of drospirenone andethinylestradiol is 21, 22, 23 or 24, and wherein the number of dailydosage units comprising ethinylestradiol alone is 7, 6, 5 or
 4. 20. Apreparation according to claim 18 or 19, wherein the at least 21 dailydosage units comprise drospirenone and ethinylestradiol in micronizedform or sprayed from a solution onto particles of an inert carrier. 21.A preparation according to claim 18, wherein the at least 21 dailydosage units comprise drospirenone in an amount of from about 2.5 mg toabout 3.5 mg, in particular about 3 mg, and ethinylestradiol in anamount of from about 0.015 mg to about 0.04 mg, in particular from about0.02 mg to about 0.03 mg.
 22. A preparation according to claim 18,wherein the at least 21 daily dosage units comprise drospirenone in anamount of from about 3.0 to about 3.5 mg and ethinylestradiol in anamount corresponding to from about 0.015 to about 0.03 mg.
 23. A methodof inhibiting ovulation in a mammal, in particular a human, comprisingadministering, to said mammal, drospirenone in an amount in the range offrom about 2 mg to about 4 mg of per day, together with ethinylestradiolin an amount of from about 0.01 mg to about 0.05 mg per day, saidamounts being effective to inhibit ovulation in said mammal.
 24. Amethod according to claim 23, wherein the amount of drospirenone is inthe range of from about 2.5 mg to about 3.5 mg, in particular about 3 mgof drospirenone per day.
 25. A method according to claim 23, wherein theamount of ethinylestradiol is from about 0.015 mg to about 0.04 mg, inparticular from about 0.015 to about 0.03 mg per day.
 26. A method ofpreventing or treating androgen-induced disorders in a female mammal, inparticular a female human, comprising administering, to said mammal, anamount of drospirenone in the range of from about 2 mg to about 4 mg perday, together with an amount of ethinylestradiol of from about 0.01 mgto about 0.05 mg per day, said amounts being effective to prevent ortreat androgen-induced disorders in said mammal.
 27. A method accordingto claim 26, wherein the androgen-induced disorder is acne.
 28. A methodof inhibiting ovulation in a mammal, in particular a human, comprisingadministering, to said mammal, on each day of at least 21 consecutivedays, a daily dosage unit comprising a combination of drospirenone in anamount of from about 2 mg to about 4 mg and ethinylestradiol in anamount from about 0.01 to about 0.05 mg, followed by administering, oneach day of 7 or less consecutive days, a daily dosage unit containingno active agent, or alternatively administering no daily dosage unitsfor 7 or less consecutive days.
 29. A method according to claim 28,wherein the daily dosage units comprising the combination ofdrospirenone and ethinylestradiol are administered for 21, 22, 23 or 24consecutive days, and wherein no daily dosage units or daily dosageunits containing no active agent are administered for 7, 6, 5 or 4consecutive days.
 30. A method according to claim 28, wherein the dailydosage units comprising the combination of drospirenone andethinylestradiol are administered for 28 consecutive days.
 31. A methodaccording to claim 28, wherein the daily dosage units comprising thecombination of drospirenone and ethinylestradiol are administered for2-4, preferably 2 or 3, times 28 consecutive days, followed byadministration of the daily dosage units comprising the combination ofdrospirenone and ethinylestradiol for 21 consecutive days andsubsequently administration of the daily dosage units containing noactive agent, or alternatively no daily dosage units, for 7 consecutivedays.
 32. A method of inhibiting ovulation in a mammal, in particular ahuman, comprising administering, to said mammal, on each day of at least21 consecutive days, a daily dosage unit comprising a combination ofdrospirenone in an amount of from about 2 mg to about 4 mg andethinylestradiol in an amount from about 0.01 to about 0.05 mg, followedby administering, on each day of 7 or less consecutive days, a dailydosage unit containing ethinylestradiol alone in an amount of from about0.01 mg to about 0.05 mg.
 33. A method according to claim 32, whereinthe daily dosage units comprising the combination of drospirenone andethinylestradiol are administered for 21, 22, 23 or 24 consecutive days,and wherein the daily dosage units comprising ethinylestradiol alone areadministered for 7, 6, 5 or 4 consecutive days.
 34. A method accordingto claim 32, wherein the daily dosage units comprising the combinationof drospirenone and ethinylestradiol are administered for 2-4,preferably 2 or 3, times 28 consecutive days, followed by administrationof the daily dosage units comprising the combination of drospirenone andethinylestradiol for 21 consecutive days and subsequently administrationof the daily dosage units comprising ethinylestradiol alone for 7consecutive days.
 35. A method of promoting rapid dissolution ofdrospirenone from a unit dosage form on oral administration, the methodcomprising providing drospirenone in micronized form in said unit dosageform, or sprayed from a solution onto particles of an inert carrier inadmixture with one or more pharmaceutically acceptable excipients thatpromote dissolution of the drospirenone.